Insulin-dependent diabetes mellitus is an autoimmune disease that causes progressive destruction of insulin-producing pancreatic b-cells. There is a compelling need for an animal model in which to develop and test immunotherapeutics for prevention and treatment of IDDM. Nonhuman primates are very similar to humans in many elements of the immune system, including highly homologous specific MHC alleles. We have investigated the potential for creating an animal model of IDDM in pigtailed macaques that carry HLA-DR3- and HLA-DR4-like class II genes. Our approach is to generate autoimmune, MHC-restricted T cells in donor animals capable of transferring diabetes to MHC-matched recipients in order to establish a model suitable for analysis of disease mechanisms and MHC and T cell-directed therapeutics. Controlled b-cell destruction was initiated in donor animals using repeated low-dose injections of streptozotocin until fasting blood glucose levels were elevated. Beta cell dam age was validated by abnormal IVGTT patterns; autoantibodies to GAD were measured and donor peripheral blood lymphocytes were studied for evidence of islet antigen reactivity. Histological sections of the pancreas failed to stain for insulin, thus demonstrating loss of insulin-secreting cells from the pancreas. In an earlier experiment, PBL were also cultured in the presence of IL-2 (10 U/ml) and PHA (2.5 5g/ml), labeled with the vital dye cell Tracker TM, and reinfused into the donor animals or into MHC-identical non-diabetic sibling animals 24 h before euthanasia. In the latter experiment, donor T cells were identified in the pancreas of the recipient animals, but not the peripheral blood, 24 h after adoptive transfer, consistent with specific homing of the activated lymphocytes for the diabetic donor. From a recent donor (J92278), we have collected 20 ( 106 cells into a recipient (J94403). A second injection of labeled donor lymphocytes is planned for the first week of April, 1999. FUNDING NIH grant RR00166.